US7482491B2 - Amino alcohol derivative, addition salt thereof, and immunosuppressant - Google Patents

Amino alcohol derivative, addition salt thereof, and immunosuppressant Download PDF

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US7482491B2
US7482491B2 US10/528,240 US52824005A US7482491B2 US 7482491 B2 US7482491 B2 US 7482491B2 US 52824005 A US52824005 A US 52824005A US 7482491 B2 US7482491 B2 US 7482491B2
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chlorophenyl
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US20060135622A1 (en
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Yasushi Kohno
Kiyoaki Tanaka
Kazuhiko Kuriyama
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Kyorin Pharmaceutical Co Ltd
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Definitions

  • the present invention relates to amino alcohol derivatives, salts and hydrates thereof that are suitable for use as immunosuppressive agents.
  • Immunosuppressive agents are widely used as a treatment for autoimmune diseases such as rheumatoid arthritis, nephritis, osteoarthritis of and systemic lupus erythematosus, chronic inflammatory diseases such as inflammatory bowel disease, and allergic diseases such as asthma and dermatitis.
  • autoimmune diseases such as rheumatoid arthritis, nephritis, osteoarthritis of and systemic lupus erythematosus
  • chronic inflammatory diseases such as inflammatory bowel disease
  • allergic diseases such as asthma and dermatitis.
  • Immunosuppressive agents also play a significant role in this aspect.
  • antimetabolites such as azathioprine and mycophenolate mofetil
  • calcineurin inhibitors such as cyclosporin A and tacrolimus
  • corticosteroid such as prednisolone
  • the present inventors conducted a search for new types of immunosuppressive agents with main interest in 2-amino-1-ethanol derivatives.
  • the present inventors discovered that novel diaryl sulfide- or diaryl ether-containing amino alcohol derivatives that have a different structure from known immunosuppressors exhibit strong immunosuppressive effects.
  • the compounds each include, at the para-position of one of the two aryl groups, a carbon chain with an amino alcohol group and also include a particular substituent at the meta-position of the other of the aryl groups.
  • the present invention thus is an immunosuppressive agent containing as an active ingredient at least one of an amino alcohol derivative, and an optical isomer, a pharmaceutically acceptable salt and a hydrate thereof, the amino alcohol derivative represented by the following general formula (1):
  • R 1 is a halogen atom, a trihalomethyl group, a lower alkyl group having 1 to 4 carbon atoms, an aralkyl group, a lower alkoxy group having 1 to 4 carbon atoms, a substituted or unsubstituted phenoxy group, a substituted or unsubstituted aralkyloxy group, a lower alkylthio group having 1 to 4 carbon atoms, a lower alkylsulfinyl group having 1 to 4 carbon atoms, or a lower alkylsulfonyl group having 1 to 4 carbon atoms;
  • R 2 is a hydrogen atom, a halogen atom, a trihalomethyl group, a lower alkyl group having 1 to 4 carbon atoms, an aralkyl group, a lower alkoxy group having 1 to 4 carbon atoms, or a aralkyloxy group;
  • R 3 is a hydrogen atom, a halogen atom,
  • the present invention concerns an immunosuppressive agent containing as an active ingredient at least one of an amino alcohol derivative represented by the following general formulae (1a):
  • the compounds of the general formulae (1), (1a), and (1b) of the present invention are each a novel compound.
  • Examples of the pharmaceutically acceptable salts of the compound of the general formula (1) in accordance with the present invention include acid-salts, such as hydrochloride, hydrobromide, acetate, trifluoroacetate, methanesulfonate, citrate, and tartrate.
  • halogen atom encompasses fluorine, chlorine, bromine, and iodine atoms.
  • trihalomethyl group encompasses trifluoromethyl and trichloromethyl.
  • lower alkyl as used in the phrases “lower alkyl group having 1 to 4 carbon atoms,” “lower alkoxy group having 1 to 4 carbon atoms,” “lower alkylthio group having 1 to 4 carbon atoms,” “lower alkylsulfinyl group having 1 to 4 carbon atoms,” and “lower alkylsulfonyl group having 1 to 4 carbon atoms” encompasses straight-chained or branched hydrocarbons having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, and t-butyl.
  • substituted or unsubstituted phenoxy group encompass those that have, at any position of its benzene ring, a halogen atom, such as fluorine, chlorine, bromine and iodine atoms, trifluoromethyl, lower alkyl having 1 to 4 carbon atoms, and lower having 1 to 4 carbon atoms.
  • a halogen atom such as fluorine, chlorine, bromine and iodine atoms, trifluoromethyl, lower alkyl having 1 to 4 carbon atoms, and lower having 1 to 4 carbon atoms.
  • aralkyl group as in “aralkyl group” or “aralkyloxy group” encompasses benzyl, diphenylmethyl, phenethyl, and phenylpropyl.
  • the phrase “lower aliphatic acyl group having 1 to 5 carbons” emcompasses straight-chained or branched lower aliphatic acyl groups having 1 to 5 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, and pivaloyl.
  • lower alkenyl group having 2 to 4 carbon atoms encompasses hydrocarbons having 2 to 4 carbon atoms and having unsaturated double bonds, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 2-methylallyl, and 3-butenyl.
  • lower alkynyl group having 2 to 4 carbon atoms encompasses hydrocarbons having 2 to 4 carbon atoms and having unsaturated triple bonds, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl.
  • the compound represented by the general formula (3) can be obtained by reacting the compound represented by the general formula (2) with the compound represented by the general formula (7) in the presence of a base (Step A):
  • R 8 represents a lower alkyl group having 1 to 4 carbon atoms, and R 1 , R 2 , R 3 , R 5 , X, and n are as described above;
  • A represents a chlorine atom, a bromine atom, an iodine atom, or a fluorine atom, and R 1 , R 2 , R 3 , X, and n are as described above];
  • This reaction uses a reaction solvent, such as methanol, ethanol, 1,4-dioxane, dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), and tetrahydrofuran (THF), and is carried out at a temperature of 0° C. to refluxing temperature, preferably 80° C. to 100° C., in the presence of inorganic base, such as sodium hydride, potassium hydride, sodium alkoxide, potassium alkoxide, potassium carbonate, and sodium carbonate.
  • a reaction solvent such as methanol, ethanol, 1,4-dioxane, dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), and tetrahydrofuran (THF)
  • DMSO dimethylsulfoxide
  • DMF N,N-dimethylformamide
  • THF tetrahydrofuran
  • the compound represented by the general formula (4) can be obtained by hydrolyzing the compound of the general formula (3) (Step B):
  • This reaction is carried out at a temperature of 0° C. to refluxing temperature in the presence of a base, such as an aqueous solution of sodium hydroxide, potassium hydroxide, or lithium hydroxide, and in a reaction solvent such as methanol, ethanol, 1,4-dioxane, DMF, or DMSO.
  • a base such as an aqueous solution of sodium hydroxide, potassium hydroxide, or lithium hydroxide
  • a reaction solvent such as methanol, ethanol, 1,4-dioxane, DMF, or DMSO.
  • the reaction is carried out at 50° C. in ethanol solvent and in the presence of potassium hydroxide.
  • R 9 represents a lower alkyl group having 1 to 4 carbon atoms, and R 1 , R 2 , R 3 , R 5 , R 8 , X, and n are as described above.
  • This reaction can be carried out by a common process to convert a carboxyl group into carbamate.
  • One such process involves ethyl chlorocarbonate and NaN 3 .
  • diphenyl phosphorazidate (DPPA) in benzene or toluene is stirred in the presence of a base such as triethylamine while the reaction mixture is heated.
  • a lower alcohol such as methanol, ethanol, propanol, isopropanol, butanol or t-butanol, is added and the mixture is further stirred while being heated.
  • a lower alcohol alone is used as the reaction solvent and the reaction mixture is stirred or refluxed while being heated.
  • This reaction uses borane (BH 3 ), an alkylborane derivative, such as 9-borabicyclo[3.3.1]nonane (9-BBN), or a metal hydride complex, such as diisobutyl aluminum hydride ((iBu) 2 AlH), sodium borohydride (NaBH 4 ), and lithium aluminum hydride (LiAlH 4 ), and preferably uses lithium borohydride (LiBH 4 ).
  • the reaction is carried out at a temperature of 0° C. to refluxing temperature, preferably at room temperature, by using THF, 1.4-dioxane, methanol, or ethanol as a reaction solvent.
  • the compound represented by the general formula (1c) can be obtained by acidolysis or hydrolysis of the compound of the general formula (6) (Step E)
  • This reaction is carried out at a temperature of 0° C. to room temperature in an inorganic or organic acid, such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, or trifluoroacetic acid, or in a mixture with an organic solvent, such as methanol, ethanol, THF, 1,4-dioxane, and ethyl acetate.
  • an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, and ethyl acetate.
  • the reaction may use methanol, ethanol, 1,4-dioxane, DMSO, DMF, or THF as a reaction solvent and is carried out at a temperature of 0° C. to refluxing temperature, preferably 80° C. to 100° C., in the presence of a base, such as an aqueous solution of sodium hydroxide, potassium hydroxide, or lithium hydroxide.
  • the compound represented by the general formula (6′) can be obtained by reducing the compound of the general formula (3) (Step D′):
  • This reaction uses an alkylborane derivative, such as BH 3 or 9-BBN, or a metal hydride complex, such as (iBu) 2 AlH, NaBH 4 , LiBH 4 , or LiAlH 4 , in particular, lithium tributoxy aluminum hydride (LiAl(t-BuO) 3 ), along with a reaction solvent such as 1,4-dioxane, ethanol, or methanol, in particular, THF.
  • a reaction solvent such as 1,4-dioxane, ethanol, or methanol, in particular, THF.
  • the compound represented by the general formula (4′) can be obtained by protecting the hydroxyl group of the compound of the general formula (6′) with methoxymethyl (MOM) group and subsequently hydrolyzing the ester (Step B′):
  • MOM represents a methoxymethyl group
  • R 1 , R 2 , R 3 , R 5 , X, and n are as described above.
  • This reaction uses a base, such as triethylamine, or pyridine, in particular, diisopropylethylamine, along with an organic solvent, such as THF, 1,4-dioxane, methylene chloride, chloroform, or acetonitrile.
  • a base such as triethylamine, or pyridine, in particular, diisopropylethylamine
  • organic solvent such as THF, 1,4-dioxane, methylene chloride, chloroform, or acetonitrile.
  • the compound of the general formula (6′) is first reacted with methoxymethyl chloride or methoxymethyl bromide at 0° C. to room temperature to introduce the MOM group.
  • the protected compound is hydrolyzed in a reaction solvent, such as methanol, ethanol, 1,4-dioxane, DMF, or DMSO, at a temperature of 0° C. to refluxing temperature and in the presence of a
  • the compound represented by the general formula (5′) can be obtained by Curtius rearrangement of the compound of the general formula (4′) (Step C′):
  • This reaction can be carried out by a common process to convert a carboxyl group into carbamate.
  • One such process involves ethyl chlorocarbonate and NaN 3 .
  • diphenyl phosphorazidate (DPPA) in benzene or toluene is stirred in the presence of a base such as triethylamine while the reaction mixture is heated.
  • a lower alcohol such as methanol, ethanol, propanol, isopropanol, butanol, or t-butanol, is added and the mixture is further stirred while being heated.
  • a lower alcohol alone is used as the reaction solvent and the reaction mixture is stirred or refluxed while being heated.
  • the compound represented by the general formula (1c) can be obtained by acidolysis or hydrolysis of the compound of the general formula (5′) (Step E′).
  • This reaction is carried out at a temperature of 0° C. to room temperature in an inorganic or organic acid, such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, or trifluoroacetic acid, or in a mixture with an organic solvent, such as methanol, ethanol, THF, 1,4-dioxane, or ethyl acetate.
  • an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, or ethyl acetate.
  • the carbamate group is first deprotected in a reaction solvent, such as methanol, ethanol, 1,4-dioxane, DMSO, DMF, or THF, at a temperature of 0° C. to refluxing temperature, preferably 80° C. to 100° C., and in the presence of a base, such as an aqueous solution of sodium hydroxide, potassium hydroxide, or lithium hydroxide.
  • R 4 is a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, a phenyl group or a substituted or unsubstituted benzyl group, and R 5 , R 6 , and R 7 are each a hydrogen atom are represented by the following general formula (1d):
  • R 10 is a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, a phenyl group, or a substituted or unsubstituted benzyl group; and R 1 , R 2 , R 3 , X, and n are as described above].
  • the compound represented by the general formula (8) can be obtained by reacting the compound represented by the general formula (2) with the compound represented by the general formula (10) in the presence of a base (Step F):
  • Boc represents t-butoxycarbonyl; and R 1 , R 2 , R 3 , R 8 , R 10 , X, and n are as described above]; and
  • This reaction uses a reaction solvent such as methanol, ethanol, 1,4-dioxane, DMSO, DMF, or THF, and is carried out at a temperature of 0° C. to refluxing temperature, preferably 80° C. to 100° C., in the presence of an inorganic base, such as sodium hydride, potassium hydride, sodium alkoxide, potassium alkoxide, potassium carbonate, or sodium carbonate.
  • a reaction solvent such as methanol, ethanol, 1,4-dioxane, DMSO, DMF, or THF
  • an inorganic base such as sodium hydride, potassium hydride, sodium alkoxide, potassium alkoxide, potassium carbonate, or sodium carbonate.
  • This reaction uses an alkylborane derivative, such as BH 3 or 9-BBN, or a metal hydride complex, such as (iBu) 2 AlH, NaBH 4 , and LiAlH 4 , in particular LiBH 4 , in a reaction solvent, such as THF, 1,4-dioxane, ethanol, or methanol.
  • a reaction solvent such as THF, 1,4-dioxane, ethanol, or methanol.
  • the compound represented by the general formula (1d) can be obtained by acidolysis of the compound of the general formula (9) (Step H).
  • This reaction is carried out at a temperature of 0° C. to room temperature in an inorganic or organic acid, such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, or trifluoroacetic acid, or in a mixture with an organic solvent, such as methanol, ethanol, THF, 1,4-dioxane, or ethyl acetate.
  • an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, or trifluoroacetic acid
  • an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, or ethyl acetate.
  • R 4 is a lower acyl group having 1 to 5 carbon atoms or a substituted or unsubstituted benzoyl group
  • R 5 , R 6 , and R 7 are each a hydrogen atom
  • R 11 is a lower aliphatic acyl group having 1 to 5 carbon atoms or a substituted or unsubstituted benzoyl group; and R 1 , R 2 , R 3 , X, and n are as described above].
  • R 1 , R 2 , R 3 , X, and n are as described above.
  • the compound represented by the following general formula (11) can be obtained by reacting the compound represented by the general formula (2) with the compound represented by the general formula (12) in the presence of a base (Step I):
  • This reaction uses a reaction solvent, such as methanol, ethanol, 1,4-dioxane, DMSO, DMF, or THF, and is carried out at a temperature of 0° C. to refluxing temperature, preferably 80° C. to 100° C., in the presence of inorganic base, such as sodium hydride, potassium hydride, sodium alkoxide, potassium alkoxide, potassium carbonate, or sodium carbonate.
  • a reaction solvent such as methanol, ethanol, 1,4-dioxane, DMSO, DMF, or THF
  • inorganic base such as sodium hydride, potassium hydride, sodium alkoxide, potassium alkoxide, potassium carbonate, or sodium carbonate.
  • the compound represented by the general formula (1e) can be obtained by reducing the compound of the general formula (11) (Step J).
  • This reaction uses an alkylborane derivative, such as BH 3 or 9-BBN, or a metal hydride complex, such as (iBu) 2 AlH, NaBH 4 , or LiAlH 4 , in particular LiBH 4 , in a reaction solvent, such as THF, 1,4-dioxane, ethanol, or methanol.
  • a reaction solvent such as THF, 1,4-dioxane, ethanol, or methanol.
  • R 4 is a hydrogen atom, a lower aliphatic acyl group having 1 to 5 carbon atoms, or a substituted or unsubstituted benzoyl group
  • R 5 is a lower alkoxymethyl group having 1 to 4 carbon atoms
  • R 6 is a hydrogen atom
  • R 12 is a hydrogen atom, a lower aliphatic acyl group having 1 to 5 carbon atoms, or a substituted or unsubstituted benzoyl group; and R 1 , R 2 , R 3 , R 7 , R 8 , X, and n are as described above].
  • R 1 , R 2 , R 3 , R 7 , R 8 , X, and n are as described above.
  • R 13 is a lower aliphatic acyl group having 1 to 5 carbons, a substituted or unsubstituted benzoyl group or Boc; and R 1 , R 2 , R 3 , X, and n are as described above]; and R 8 -A (13) [wherein R 8 and A are as described above].
  • This reaction may use a reaction solvent such as methylene chloride, THF, or 1,4-dioxane and is carried out at 0° C. to room temperature in the presence of a base, such as triethylamine or pyridine.
  • a base such as triethylamine or pyridine.
  • the reaction is carried out at room temperature in acetonitrile and in the presence of silver oxide.
  • R 13 in the general formula (9c) is Boc
  • the acidolysis is carried out at a temperature of 0° C.
  • an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, or trifluoroacetic acid
  • an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, or ethyl acetate.
  • R 5 is a lower alkoxymethyl group having 1 to 4 carbon atoms or a lower alkylthiomethyl group having 1 to 4 carbon atoms
  • R 4 , R 6 and R 7 are each a hydrogen atom
  • the compound represented by the following general formula (14) can be obtained from the compound represented by the following general formula (9a′), which is the general formula (9a) with R 10 being a hydrogen atom (Step K):
  • This reaction uses a reaction solvent such as THF, 1,4-dioxane, DMF, benzene, or toluene and is carried out at a temperature of 0° C. to refluxing temperature, preferably at room temperature, in the presence of an inorganic base, such as sodium hydride, potassium hydride, sodium alkoxide, or potassium alkoxide.
  • a reaction solvent such as THF, 1,4-dioxane, DMF, benzene, or toluene
  • an inorganic base such as sodium hydride, potassium hydride, sodium alkoxide, or potassium alkoxide.
  • the reaction may be carried out in pyridine solvent while the reaction mixture is refluxed, preferably at 80° C. to 100° C.
  • the compound represented by the following general formula (15) can be obtained by substituting the hydroxyl group of the compound of the general formula (14) with a halogen atom (Step L):
  • R 1 , R 2 , R 3 , A, X, and n are as described above.
  • the reaction uses a reaction solvent such as methylene chloride, THF, or 1,4-dioxane and is carried out at 0° C. to room temperature.
  • a reaction solvent such as methylene chloride, THF, or 1,4-dioxane
  • the compound of the general formula (14) is reacted with carbon tetrachloride, carbon tetrabromide, or iodine in the presence of triphenylphosphine or imidazole.
  • the compound of the general formula (14) may be reacted with para-toluene sulfonyl chloride or methanesulfonyl chloride in a solvent such as methylene chloride, chloroform, or benzene in the presence of an organic base such as pyridine or triethylamine to form a corresponding sulfonic acid ester.
  • the reaction is carried out at 0° C. to 80° C., preferably at room temperature.
  • the resulting sulfonic acid ester is reacted with sodium bromide, potassium bromide, sodium iodide, potassium iodide, potassium fluoride, or sodium fluoride.
  • This reaction uses a reaction solvent such as THF, acetonitrile and, preferably, acetone and is carried out at room temperature to refluxing temperature.
  • the compound represented by the following general formula (16) can be obtained by reacting the compound of the general formula (15) with the compound represented by the following general formula (18) (Step M):
  • R 1 , R 2 , R 3 , R 8 , X, Y, and n are as described above
  • R 8 —YH (18) [wherein R 8 and Y are as described above].
  • This reaction uses a reaction solvent such as methanol, ethanol, 1,4-dioxane, or DMF and is carried out at 0° C. to room temperature in the presence of an organic base, such as triethylamine or pyridine, or an inorganic base, such as sodium hydride, sodium methoxide, sodium ethoxide, sodium butoxide, or potassium butoxide.
  • a reaction solvent such as methanol, ethanol, 1,4-dioxane, or DMF
  • an organic base such as triethylamine or pyridine
  • an inorganic base such as sodium hydride, sodium methoxide, sodium ethoxide, sodium butoxide, or potassium butoxide.
  • the ring-opening reaction uses a reaction solvent such as THF or 1,4-dioxane, preferably acetonitrile and is carried out under typical Boc-adding conditions.
  • the reaction is carried out by first applying Boc 2 O at room temperature to 80° C. in the presence of dimethylaminopyridien to form a Boc-added form and subsequently opening the oxazolidinone ring at room temperature in methanol solvent in the presence of cesium carbonate.
  • the compound represented by the general formula (1g) can be obtained by acidolysis of the compound of the general formula (17) (Step O).
  • This reaction is carried out at a temperature of 0° C. to room temperature in an inorganic or organic acid, such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, or trifluoroacetic acid, or in a mixture with an organic solvent, such as methanol, ethanol, THF, 1,4-dioxane, or ethyl acetate.
  • an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, or trifluoroacetic acid
  • an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, or ethyl acetate.
  • this reaction uses methylene chloride as a reaction solvent and is carried out at room temperature by adding Ph 3 Bi(OAc) 2 and, if necessary, molecular sieves, in the presence of copper acetate.
  • R 4 is a hydrogen atom, a lower aliphatic acyl group having 1 to 5 carbon atoms, or a substituted or unsubstituted benzoyl group
  • R 5 is a lower alkenyl group having 2 to 4 carbon atoms
  • R 6 and R 7 are each a hydrogen atom
  • one of the hydroxyl groups is first protected by a common hydroxyl-protecting group, including an acyl-type protecting group, such as acetyl and benzoyl, a silyl-type protecting group, such as t-butyldimethylsilyl and t-butyldiphenylsilyl, and an alkyl-type protecting group, such as benzyl.
  • a common hydroxyl-protecting group including an acyl-type protecting group, such as acetyl and benzoyl, a silyl-type protecting group, such as t-butyldimethylsilyl and t-butyldiphenylsilyl, and an alkyl-type protecting group, such as benzyl.
  • DMSO oxidation is then performed to obtain an aldehyde.
  • oxidizing agent including chromium oxide-pyridine complex, such as pyridinium chlorochromate or pyridinium dichromate, a metal oxidizing agent, such as chromium oxide, silver carbonate, or manganese dioxide, or a DMSO activating agent, such as oxalyl chloride, trifuluoroacetic anhydride, acetic anhydride, DCC, or sulfur trioxide-pyridine complex.
  • chromium oxide-pyridine complex such as pyridinium chlorochromate or pyridinium dichromate
  • metal oxidizing agent such as chromium oxide, silver carbonate, or manganese dioxide
  • DMSO activating agent such as oxalyl chloride, trifuluoroacetic anhydride, acetic anhydride, DCC, or sulfur trioxide-pyridine complex.
  • the Wittig reaction uses a reaction solvent such as THF, ether, DMSO, or 1,4-dioxane in conjunction with a phosphonium salt having a lower alkyl group such as methyl, ethyl, propyl isopropy, or butyl and is carried out at ⁇ 78° C. to room temperature in the presence of a base, such as sodium hydride, potassium hydride, sodium butoxide, potassium butoxide, or lithium diisopropylamide.
  • a reaction solvent such as THF, ether, DMSO, or 1,4-dioxane
  • a phosphonium salt having a lower alkyl group such as methyl, ethyl, propyl isopropy, or butyl
  • a base such as sodium hydride, potassium hydride, sodium butoxide, potassium butoxide, or lithium diisopropylamide.
  • the subsequent deprotection of hydroxyl group uses a reaction solvent such as methanol, ethanol, 1,4-dioxane, DMSO, DMF, or THF and is carried out at 0° C. to room temperature in the presence of a base, such as an aqueous solution of sodium hydroxide, potassium hydroxide, or lithium hydroxide.
  • a reaction solvent such as methanol, ethanol, 1,4-dioxane, DMSO, DMF, or THF
  • a base such as an aqueous solution of sodium hydroxide, potassium hydroxide, or lithium hydroxide.
  • THF, DMF or 1,4-dioxane is used as a solvent and the deprotection reaction is carried out by applying potassium fluoride, cesium fluoride, or tetrabutylammonium fluoride at 0° C. to room temperature.
  • the deprotection is carried out by a common contact reduction process.
  • the deprotection is carried out in an inorganic or organic acid, such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, or trifluoroacetic acid, or in a mixture with an organic solvent, such as methanol, ethanol, THF, 1,4-dioxane, or ethyl acetate.
  • R 13 in the general formula (9c) is a Boc group
  • it may be removed by carrying out acidolysis in an inorganic or organic acid, such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, or trifluoroacetic acid, or in a mixture with an organic solvent, such as methanol, ethanol, THF, 1,4-dioxane, or ethyl acetate.
  • an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, or trifluoroacetic acid
  • an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, or ethyl acetate.
  • R 4 is a hydrogen atom, a lower aliphatic acyl group having 1 to 5 carbon atoms, or a substituted or unsubstituted benzyl group
  • R 6 is a lower alkyl group having 1 to 4 carbon atoms
  • R 7 is a hydrogen atom
  • the oxidation can be carried out by using any methods commonly used for oxidizing an alcohol to an aldehyde.
  • an oxiding agent including a chromium oxide-pyridine complex, such as pyridinium chlorochromate or pyridinium dichromate, a metal oxiding agent, such as chromium oxide, silver carbonate and manganese dioxide, or a DMSO activating agent, such as oxalyl chloride, trifuluoroacetic anhydride, acetic anhydride, DCC and sulfur trioxide-pyridine complex.
  • the resulting aldehyde is reacted with a lower alkyl lithium or a lower alkyl Grignard reagent having methyl, ethyl, propyl, isopropyl, or butyl.
  • the reaction is carried out at 0° C. to room temperature in a reaction solvent such as THF, ether, or 1,4-dioxane.
  • R 13 is a Boc group
  • the deprotection is carried out at 0° C.
  • R 13 is a lower aliphatic acyl group or a substituted or unsubstituted benzoyl group that requires deprotection, the deprotection is carried out at 0° C. to refluxing temperature, preferably at 80° C.
  • reaction solvent such as methanol, ethanol, 1,4-dioxane, DMSO, DMF, or THF
  • base such as an aqueous solution of sodium hydroxide, potassium hydroxide, or lithium hydroxide
  • the compound represented by the general formula (1k) can also be obtained by the following alternative synthetic pathway:
  • This reaction uses an oxidizing agent, such as potassium permanganate, lead tetraacetate, luthenium tetraoxide, or, preferably, chromium oxide-pyridine complex, such as pyridinium chlorochromate or pyridinium dichromate, and is carried out at 0° C. to room temperature in a reaction solvent, such as acetone, DMF, methylene chloride, chloroform, ethyl acetate, or acetic acid.
  • an oxidizing agent such as potassium permanganate, lead tetraacetate, luthenium tetraoxide, or, preferably, chromium oxide-pyridine complex, such as pyridinium chlorochromate or pyridinium dichromate
  • the compound represented by the following general formula (20) can be obtained by condensation of N,O-dimethylhydroxylamine with the compound of the general formula (19) (Step Q):
  • This reaction can be carried out by using acid anhydride mixture method or active ester method, each commonly used in forming peptide bonds, and preferably involves a condensation agent.
  • the reaction uses a reaction solvent such as THF, DMSO, DMF, or methylene chloride and is carried out at 0° C.
  • an organic base such as triethylamine or pyridine
  • a condensation agent such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), DPPA, diethylphosphonylcyanide (DEPC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC), with 4-dimethylaminopyridine (DMAP) optionally added as a catalyst.
  • DCC dicyclohexylcarbodiimide
  • DIPC diisopropylcarbodiimide
  • DPPA diethylphosphonylcyanide
  • DEPC diethylphosphonylcyanide
  • WSC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
  • DMAP 4-dimethylaminopyridine
  • the compound represented by the following general formula (21) can be obtained by reacting the compound of the general formula (20) with the compound represented by the following general formula (22) (Step R):
  • R 1 , R 2 , R 3 , R 5 , R 8 , R 13 , X, and n are as described above
  • R 8 -M (22) [wherein M represents Li, MgCl, MgBr, or MgI and R 8 is as described above].
  • the reaction uses a organic solvent such as ether, 1,4-dioxane, or THF and is carried out at ⁇ 78° C. to room temperature.
  • a organic solvent such as ether, 1,4-dioxane, or THF
  • the compound represented by the general formula (1k) can be obtained by reducing the compound of the general formula (21), followed, if necessary, by deprotection.
  • This reaction uses an alkylborane derivative, such as BH 3 or 9-BBN, or a metal hydride complex, such as (iBu) 2 AlH, NaBH 4 , or LiAlH 4 , in particular, LiBH 4 , in particular, LiBH 4 , in a reaction solvent such as THF, 1,4-dioxane, ethanol, or methanol.
  • a reaction solvent such as THF, 1,4-dioxane, ethanol, or methanol.
  • R 13 is a lower aliphatic acyl group or a substituted or unsubstituted benzoyl group that requires deprotection, the deprotection is carried out at 0° C. to refluxing temperature, preferably at 80° C.
  • reaction solvent such as methanol, ethanol, 1,4-dioxane, DMSO, DMF, or THF
  • base such as an aqueous solution of sodium hydroxide, potassium hydroxide, or lithium hydroxide
  • R 4 is a lower acyl group having 1 to 5 carbon atoms or a substituted or unsubstituted benzyl group are represented by the following general formula (1m):
  • R 14 is a lower alkyl group having 1 to 4 carbon atoms or a substituted or unsubstituted phenyl group; and Z is a halogen atom or a hydroxyl group].
  • the reaction can be carried out by using acid anhydride mixture method or active ester method, each commonly used in forming peptide bonds, and preferably involves a condensation agent.
  • the reaction uses a reaction solvent such as THF, DMSO, DMF, or methylene chloride and is carried out at 0° C. to room temperature in the presence of an organic base such as triethylamine or pyridine, along with a condensation agent such as DCC, DIPC, DPPA, DEPC, or WSC, with DMAP optionally added as a catalyst.
  • the reaction uses a reaction solvent such as THF, methylene chloride, or 1,4-dioxane and is carried out at 0° C. to room temperature in the presence of an organic base such as triethylamine or pyridine.
  • a reaction solvent such as THF, methylene chloride, or 1,4-dioxane
  • R 4 is a lower alkyl group having 1 to 4 carbon atoms or a substituted or unsubstituted benzyl group are represented by the following general formula (1o):
  • R 15 is a lower alkyl group having 1 to 4 carbon atoms or a substituted or unsubstituted benzyl group; and R 1 , R 2 , R 3 , R 5 , R 6 , X, and n are as described above].
  • R 1 , R 2 , R 3 , R 5 , R 6 , X, and n are as described above.
  • This reaction uses a metal hydride complex, such as BH 3 , NaBH 4 , or LiBH 4 , in particular, LiAlH 4 , along with a reaction solvent such as THF or 1,4-dioxane.
  • a metal hydride complex such as BH 3 , NaBH 4 , or LiBH 4 , in particular, LiAlH 4
  • the reaction is carried out at a temperature of 0° C. to refluxing temperature.
  • the compound represented by the following general formula (24) can be obtained by reacting the compound of the general formula (14) with methanesulfonyl chloride or p-toluenesulfonyl chloride (Step T):
  • R 16 is a methanesulfonyl or toluenesulfonyl group; and R 1 , R 2 , R 3 , X, and n are as described above].
  • This reaction may be solvent-free or may use an organic solvent such as methylene chloride, chloroform, benzene, toluene, or THF and is carried out at 0° C. to room temperature in the presence of an organic base such as triethylamine, diisopropylethylamine, or pyridine.
  • organic solvent such as methylene chloride, chloroform, benzene, toluene, or THF
  • the compound represented by the following general formula (25) can be obtained by reacting the compound of the general formula (24) with sodium cyanide or potassium cyanide (Step U):
  • This reaction uses a solvent such as 1,4-dioxane, DMSO, or DMF and is carried out at room temperature to 80° C. and, if necessary, in the presence of water.
  • a solvent such as 1,4-dioxane, DMSO, or DMF
  • the compound represented by the following general formula (26) can be obtained either by hydrolysis of the compound of the general formula (25), followed by introduction of a Boc group and reduction, or by introduction of a Boc group to the compound of the general formula (25), followed by ring-opening of the oxazolidinone ring and reduction, as shown in Step N (Step V):
  • This reaction uses a reaction solvent such as methanol, ethanol, 1,4-dioxane, DMSO, DMF, or THF and is carried out at 0° C. to refluxing temperature, preferably at 80° C. to 100° C., in the presence of a base, such as an aqueous solution of sodium hydroxide, potassium hydroxide, or lithium hydroxide.
  • a base such as an aqueous solution of sodium hydroxide, potassium hydroxide, or lithium hydroxide.
  • Boc 2 O is applied at room temperature, to carry out a typical process for adding Boc group.
  • the reaction is then carried out at 0° C.
  • a metal hydride complex such as BH 3 , NaBH 4 , or LiBH 4 , in particular LiAlH 4
  • a reaction solvent such as THF or 1,4-dioxane.
  • Boc 2 O is applied at room temperature to 80° C., preferably in the presence of dimethylamino pyridine, to obtain a Boc-added form, which is followed by ring-opening of the oxazolidinone ring, carried out at room temperature in the presence of cesium carbonate in methanol as a solvent.
  • the reaction is then carried out at 0° C. to refluxing temperature in the presence of a metal hydride complex, such as BH 3 , NaBH 4 , or LiBH 4 , in particular LiAlH 4 , in a reaction solvent such as THF or 1,4-dioxane.
  • the compound represented by the general formula (1p) can be obtained by acidolysis of the compound of the general formula (26) (Step W).
  • This reaction is carried out at a temperature of 0° C. to room temperature in an inorganic or organic acid, such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, or trifluoroacetic acid, or in a mixture with an organic solvent, such as methanol, ethanol, THF, 1,4-dioxane, or ethyl acetate.
  • an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, or trifluoroacetic acid
  • an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, or ethyl acetate.
  • R 5 is a hydroxypropyl group
  • R 4 is a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, a phenyl, or a substituted or unsubstituted benzyl group
  • R 6 and R 7 are each a hydrogen atom
  • the compound represented by the following general formula (27) can be obtained by reacting the compound of the general formula (9a) with methoxymethyl chloride, t-butyldimethylsilyl chloride, t-butyldiphenylsilyl chloride, or triisopropylsilyl chloride (Step a):
  • R 17 is a methoxymethyl group, a t-butyldimethylsilyl group, a t-butyldiphenylsilyl group, or a triisopropylsilyl group; and R 1 , R 2 , R 3 , R 10 , Boc, X, and n are as described above].
  • This reaction uses an organic solvent such as acetonitrile, THF, methylene chloride, or chloroform and is carried out at 0° C. to room temperature in the presence of an organic base such as triethylamine or diisopropylethylamine.
  • organic solvent such as acetonitrile, THF, methylene chloride, or chloroform
  • R 1 , R 2 , R 3 , R 10 , R 17 , Boc, X, and n are as described above.
  • This reaction is carried out by performing DMSO oxidation using an oxidizing agent, including chromium oxide-pyridine complex, such as pyridinium chlorochromate or pyridinium dichromate, a metal oxiding agent, such as chromium oxide, silver carbonate, or manganese dioxide, or a DMSO activating agent, such as oxalyl chloride, trifuluoroacetic anhydride, acetic anhydride, DCC and sulfur trioxide-pyridine complex.
  • an oxidizing agent including chromium oxide-pyridine complex, such as pyridinium chlorochromate or pyridinium dichromate, a metal oxiding agent, such as chromium oxide, silver carbonate, or manganese dioxide, or a DMSO activating agent, such as oxalyl chloride, trifuluoroacetic anhydride, acetic anhydride, DCC and sulfur trioxide-pyridine complex.
  • the compound represented by the following general formula (29) can be obtained by reacting the compound of the general formula (28) with the compound represented by the following general formula (31) in the presence of a base (Step c):
  • This reaction is carried out by first reacting the compound of the general formula (31) with a base such as sodium hydride, potassium hydride, sodium butoxide, or potassium butoxide at 0° C. to room temperature in an organic solvent such as THF, DMSO, or 1,4-dioxane, and subsequently applying the compound of the general formula (29).
  • a base such as sodium hydride, potassium hydride, sodium butoxide, or potassium butoxide
  • This reaction is carried out by first reducing the double bonds at room temperature to 100° C. under a hydrogen pressure of atmospheric or higher pressure in the presence of a reduction catalyst, such as palladium carbon, platinum carbon, platinum oxide, rhodium carbon, or ruthenium carbon, in a solvent such as ethanol, methanol, THF, DMF, or ethyl acetate.
  • a reduction catalyst such as palladium carbon, platinum carbon, platinum oxide, rhodium carbon, or ruthenium carbon
  • ester bonds are reduced by using an alkylborane derivative, such as BH 3 or 9-BBN, or a metal hydride complex, such as (iBu) 2 AlH, NaBH 4 , LiBH 4 , or LiAlH 4 in a reaction solvent such as 1,4-dioxane, ethanol, or methanol and, preferably, THF.
  • an alkylborane derivative such as BH 3 or 9-BBN
  • a metal hydride complex such as (iBu) 2 AlH, NaBH 4 , LiBH 4 , or LiAlH 4
  • a reaction solvent such as 1,4-dioxane, ethanol, or methanol and, preferably, THF.
  • the compound represented by the general formula (1q) can be obtained by acidolysis of the compound of the general formula (30) (Step e).
  • R 17 is a silyl protective group
  • this reaction is carried out by first applying tetrabutylammonium fluoride or potassium fluoride in a THF solvent at 0° C. to room temperature. Subsequently, the acidolysis is carried out at 0° C. to room temperature in an inorganic or organic acid, such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, or trifluoroacetic acid, or in a mixture with an organic solvent, such as methanol, ethanol, THF, 1,4-dioxane, or ethyl acetate.
  • an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, or ethyl acetate.
  • the compound represented by the following general formula (32) can be obtained by the introduction of Boc group to the compound of the general formula (15), followed by ring-opening of the oxazolidinone ring (Step f):
  • This reaction uses a reaction solvent such as THF, 1,4-dioxane, or, preferably, acetonitrile and is carried out under typical conditions for Boc introduction.
  • Boc 2 O is applied at room temperature to 80° C. to obtain a Boc-added form, which is followed by ring-opening of the oxazolidinone ring, carried out at room temperature in the presence of cesium carbonate in methanol.
  • the compound represented by the general formula (1r) can be obtained either by acidolysis of the compound of the general formula (32) (Step h) or by hydrolysis of the compound of the general formula (15) (Step g).
  • the acidolysis of the compound of the general formula (32) is carried out at 0° C. to room temperature in an inorganic or organic acid, such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, or trifluoroacetic acid, or in a mixture with an organic solvent, such as methanol, ethanol, THF, 1,4-dioxane, or ethyl acetate.
  • the hydrolysis of the compound of the general formula (15) is carried out at a temperature of 0° C. to refluxing temperature, preferably at 80° C.
  • a base such as aqueous solution of sodium hydroxide, potassium hydroxide, or lithium hydroxide
  • a reaction solvent such as methanol, ethanol, 1,4-dioxane, DMSO, DMF, or THF.
  • This reaction uses a reaction solvent such as 1,4-dioxane, DMSO, DMF, THF, methylene chloride, or chloroform, along with an oxidizing agent such as potassium permanganate, meta-chloroperbenzoic acid, or aqueous hydrogen peroxide, and icarried out at 0° C. to refluxing temperature and, preferably, at room temperature.
  • a reaction solvent such as 1,4-dioxane, DMSO, DMF, THF, methylene chloride, or chloroform
  • an oxidizing agent such as potassium permanganate, meta-chloroperbenzoic acid, or aqueous hydrogen peroxide
  • the compound of Reference Example 92 (840 mg) was dissolved in methylene chloride (20 mL). While the solution was stirred at 0° C., a 1 mol/L methylene chloride solution of tribromoboron (3.42 mL) was added dropwise. The reaction mixture was stirred at room temperature overnight. Subsequently, ice water was added, and the mixture was extracted with ethyl acetate and was washed sequentially with water and a saturated aqueous solution of sodium chloride. The organic phase was dried over anhydrous sodium sulfate. The solvent was then removed under reduced pressure to give 4′-(3-trifluoromethyl-5-hydroxyphenoxy)dihydrocinnamate as a pale brown powder (750 mg).
  • the resulting powder was dissolved in DMF (50 mL). To this solution, potassium carbonate (1.04 g) and benzyl bromide (0.602 mL) were added and the mixture was stirred at room temperature for 8 hours. Subsequently, the reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate and was washed sequentially with water and a saturated aqueous solution of sodium chloride. The organic phase was then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the desired product as a brown oil.
  • the compound of Reference Example 97 (7.40 g) was dissolved in THF (100 mL). While this solution was stirred at 0° C., lithium aluminum hydride (500 mg) was added. After 10 min, a 20% aqueous solution of NaOH was added and the separated insoluble inorganic residue was removed by filtration through Celite. The filtrate was extracted with ethyl acetate and the extract was washed sequentially with water and a saturated aqueous solution of sodium chloride. The organic phase was then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the desired product as a colorless oil (6.37 g).
  • the compound of Reference Example 99 (1.38 g) was dissolved in THF (20 mL). While this solution was stirred at 0° C., imidazole (545 mg), triphenylphosphine (2.10 g), and iodine (2.00 g) were added. The mixture was stirred for 2 hours at this temperature and for the subsequent 1.5 hours at room temperature, and additional imidazole (160 mg), triphenyl phosphine (600 mg), and iodine (500 mg) were added. The mixture was stirred overnight, followed by the addition of water and then sodium thiosulfate.
  • reaction mixture was then extracted with ethyl acetate and the extract was washed sequentially with water and a saturated aqueous solution of sodium chloride.
  • the organic phase was then dried over anhydrous sodium sulfate.
  • the compound of Reference Example 31 was treated in the same manner as in Reference Example 99 to obtain an alcohol.
  • the alcohol (5.64 g) was dissolved in methylene chloride (100 mL) and phosphorus tribromide (2.25 mL) was added dropwise. Following stirring at room temperature for 1 hour, ice water was added and the mixture was extracted with ethyl acetate. The extract was washed sequentially with water and an aqueous solution of sodium chloride, and the organic phase was dried over anhydrous sodium sulfate. The solvent was removed to obtain a pale yellow oil.
  • the cyano-product (3.81 g) and potassium hydroxide (3.68 g) were added to a mixture of ethanol (80 mL), and water (10 mL), and the solution was refluxed for 6 hours. Subsequently, the solution was allowed to cool and the insoluble material was removed by filtration. The filtrate was neutralized with diluted hydrochloric acid. This mixture was extracted with ethyl acetate and the extract was washed sequentially with water and a saturated aqueous solution of sodium chloride. The organic phase was then dried over anhydrous sodium sulfate. The solvent was removed and ethanol (50 mL) and thionyl chloride (2 mL) were added to the resulting residue.
  • Example 37 The compound of Example 37 was reduced in the same manner as in Reference Example 65.
  • the extract was washed sequentially with water and a saturated aqueous solution of sodium chloride.
  • the organic phase was then dried over anhydrous magnesium sulfate.
  • Example 39 In a similar manner to Example 39, the compounds of Examples 2 through 36 and 38 were used to synthesize the compounds shown in Table 7 below.
  • Example 121 The compound of Example 121 (1.47 g) was dissolved in THF (30 mL), followed by the addition of NaSMe (210 mg) and stirring 2 hours at room temperature. Subsequently, water was added and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and the organic phase was dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to give the desired product as a colorless oil (1.27 g).
  • Example 124 Using the compound of Example 124, the reaction was carried out in the same manner as in Example 123 to give the desired product as a colorless oil.
  • Example 126 Using the compound of Example 126, the reaction was carried out in the same manner as in Example 39 to give the desired product as a colorless oil.
  • Example 75 The compound of Example 75 (500 mg) was dissolved in methylene chloride (10 mL). To this solution, pyridine (0.2 mL) and benzoylchloride (0.12 mL) were added and the mixture was stirred at room temperature for 1 hour. Following addition of water, the reaction mixture was extracted with ethyl acetate and the extract was washed sequentially with water and a saturated aqueous solution of sodium chloride. The organic phase was then dried over anhydrous sodium sulfate. The solvent was concentrated and the residue was dissolved in methanol (20 mL). To this solution, ethyl acetate containing 3 mol/L hydrochloric acid (10 mL) was added and the mixture was stirred at room temperature for 1 hour. After concentration, a saturated aqueous solution of sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate to give the desired product as a colorless oil (670 mg
  • Example 129 The compound of Example 129 (2.67 g) was dissolved in ethanol (100 mL). To this solution, a 1 mol/L aqueous solution of sodium hydroxide (20 mL) was added and the mixture was stirred at room temperature for 1 hour. Subsequently, hydrochloric acid was added to make the solution acidic and the mixture was extracted with ethyl acetate. The extract was washed sequentially with water and a saturated aqueous solution of sodium chloride, and the organic phase was dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to give the carboxylic acid product as a colorless oil (2.60 g).
  • Example 131 The compound of Example 131 was reacted in the same manner as in Example 76 to give the desired product as a brown amorphous.
  • Example 133 In the same manner as in Example 131, the compound of Example 133 was used to give the desired product as a colorless oil.
  • Example 134 In the same manner as in Example 76, the compound of Example 134 was used to give the desired product as a pale brown oil.
  • Example 76 In the same manner as in Example 76, the compounds of 112 through 119, 123 and 125 were used to synthesize the compounds in Table 10 below.
  • Example 146 To the compound of Example 146 (196 mg), a 3 mol/L aqueous solution of sodium hydroxide (5 mL) and ethanol (0.5 mL) were added and the mixture was refluxed for 8 hours. While the mixture was stirred in an ice bath, 4 mol/L hydrochloric acid was added to adjust the pH of the mixture to 2 to 1. Using ethyl acetate and water, the mixture was separated into an organic phase and an aqueous phase. The organic layer was dried over anhydrous sodium sulfate, was concentrated, and was dried in a vacuum pump to give the desired product as a pale white solid (201 mg).
  • Example 166 Using the compound of Reference Example 166, the reaction was carried out in the same manner as in Example 152 to give the desired product as a pale yellow oil.
  • Example 166 Using the compound of Reference Example 166, the reaction was carried out in the same manner as in Example 153 to give the desired product as a colorless oil.
  • Example 153 Using the compound of Example 153, the reaction was carried out in the same manner as in Example 156 to give the desired product as a yellow oil.
  • Example 154 Using the compound of Example 154, the reaction was carried out in the same manner as in Example 156 to give the desired product as a pale yellow oil.
  • Example 155 Using the compound of Example 155, the reaction was carried out in the same manner as in Example 156 to give the desired product as a pale yellow oil.
  • Example 157 Using the compound of Example 157, the reaction was carried out in the same manner as in Example 163 to give the desired product as a yellow oil.
  • Example 158 Using t-butanol in place of methanol, the compound of Example 158 was reacted in the same manner as in Example 163 to give the desired product as a pale yellow oil.
  • Example 159 Using the compound of Example 159, the reaction was carried out in the same manner as in Example 163 to give the desired product as a pale yellow oil.
  • Example 163 Using the compound of Example 163, the reaction was carried out in the same manner as in Example 39 to give the desired product as a colorless oil.
  • Example 164 Using the compound of Example 164, the reaction was carried out in the same manner as in Example 39 to give the desired product as a pale yellow oil.
  • Example 165 Using the compound of Example 165, the reaction was carried out in the same manner as in Example 39 to give the desired product as a colorless oil.
  • Example 166 Using the compound of Example 166, the reaction was carried out in the same manner as in Example 39 to give the desired product as a colorless oil.
  • Example 178 was optically resolved under similar conditions to Examples 173 and 174.
  • a mixed solvent composed of a 5 mol/L aqueous solution of potassium hydroxide (2 mL), tetrahydrofuran (2 mL), and methanol
  • Example 170 Using the compound of Example 170, the reaction was carried out in the same manner as in Example 184 to give the desired product as a pale yellow oil.
  • Example 171 Using the compound of Example 171, the reaction was carried out in the same manner as in Example 184 to give the desired product as a pale yellow oil.
  • Example 157 Using t-butanol in place of methanol, the compound of Example 157 was reacted in the same manner as in Example 163, followed by reduction to give the desired product as a colorless oil.
  • Example 187 Using the compound of Example 187, the reaction was carried out in the same manner as in Example 76 to give the desired product as a pale yellow amorphous.
  • Example 173 Using the compound of Example 173, the reaction was carried out in the same manner as in Example 184 to give the desired product as a pale yellow oil.
  • Example 174 Using the compound of Example 174, the reaction was carried out in the same manner as in Example 184 to give the desired product as a pale yellow oil.
  • Example 175 Using the compound of Example 175, the reaction was carried out in the same manner as in Example 76 to give the desired product as a colorless powder.
  • Example 176 Using the compound of Example 176, the reaction was carried out in the same manner as in Example 76 to give the desired product as a colorless powder.
  • Example 177 Using the compound of Example 177, the reaction was carried out in the same manner as in Example 76 to give the desired product as a colorless powder.
  • Example 178 Using the compound of Example 178, the reaction was carried out in the same manner as in Example 184 to give the desired product as a pale yellow oil.
  • Example 180 Using the compound of Example 180, the reaction was carried out in the same manner as in Example 184 to give the desired product as a colorless oil.
  • Example 179 Using the compound of Example 179, the reaction was carried out in the same manner as in Example 184 to give the desired product as a colorless oil.
  • a methylene chloride solution (30 mL) containing the compound of Example 101 (900 mg), p-chlorobenzoic acid (470 mg), WSC (575 mg), and triethylamine (0.84 mL) was stirred at room temperature for 8 hours. Subsequently, water was added and the mixture was extracted with ethyl acetate. The extract was washed sequentially with water, diluted hydrochloric acid, water, a saturated aqueous solution of sodium bicarbonate, and a saturated aqueous solution of sodium chloride. The organic phase was then dried over anhydrous sodium sulfate. The solvent was concentrated and the residue was purified on a silica gel column chromatography (hexane:ethyl acetate 1:1) to obtain the desired product as a colorless oil (800 mg).
  • Example 201 The N,O-diacetylated product (1.00 g) obtained in Example 201 was dissolved in tetrahydrofuran (10 mL). To this solution, lithium aluminum hydride (191 mg) was added while the solution was chilled on an ice bath. The mixture was stirred for 2 hours. Subsequently, a 1 mol/L aqueous solution of potassium hydroxide was added dropwise. This was followed by the addition of water to dilute the mixture. The mixture was then filtrated through Celite and the solvent was concentrated. The residue was purified on a silica gel column chromatography (aminated silica gel, ethyl acetate) to give the desired product as a colorless oil (210 mg).
  • Example 203 Using the compound of Example 203, the reaction was carried out in the same manner as in Example 76 to give the desired product as a yellow powder.
  • Example 204 Using the compound of Example 204, the reaction was carried out in the same manner as in Example 76 to give the desired product as a pale yellow powder.
  • Example 208 Using the compound of Example 208, the reaction was carried out in the same manner as in Example 76 to give the desired product as a colorless powder.
  • Example 211 Using the compound of Example 211, the reaction was carried out in the same manner as in Example 212 to give the desired product as a colorless oil.
  • Example 213 Using the compound of Example 213, the reaction was carried out in the same manner as in Example 214 to give the desired product as a yellow oil.
  • Example 2115 Using the compound of Example 215, the reaction was carried out in the same manner as in Example 216 to give the desired product as a yellow oil.
  • Example 216 Using the compound of Example 216, the reaction was carried out in the same manner as in Example 163 to give the desired product as a colorless oil.
  • Example 217 Using the compound of Example 217, the reaction was carried out in the same manner as in Example 163 to give the desired product as a yellow oil.
  • Example 2128 Using the compound of Example 218, the reaction was carried out in the same manner as in Example 184 to give the desired product as a colorless oil.
  • Example 219 Using the compound of Example 219, the reaction was carried out in the same manner as in Example 184 to give the desired product as a colorless oil
  • Example 220 Using the compound of Example 220, the reaction was carried out in the same manner as in Example 76 to give the desired product as a colorless amorphous.
  • Example 221 Using the compound of Example 221, the reaction was carried out in the same manner as in Example 76 to give the desired product as a colorless oil.
  • Example 224 Using the compound of Example 224, the reaction was carried out in the same manner as in Example 133 to give the desired product as a colorless oil.
  • EtPh 3 PI (906 mg) was dissolved in THF (20 mL). To this solution, LDA (2.20 mL), chilled to ⁇ 78° C., was added under atmosphere of argon gas and the mixture was stirred for 10 min. Subsequently, the mixture was stirred at 0° C. for 5 min and was then chilled again to ⁇ 78° C., followed by the dropwise addition of a THF solution (10 mL) of the compound of Example 225 (1.00 g). The mixture was further stirred at ⁇ 78° C. for 1 hour and at room temperature for 1 hour. Following addition of water, the mixture was extracted with ethyl acetate and the extract was washed with a saturated aqueous solution of sodium chloride.
  • Example 2266 Using the compound of Example 226, the reaction was carried out in the same manner as in Example 76 to give the desired product as a colorless oil.
  • An ammonium chloride-Tris isotonic buffer was added to the suspension to lyse erythrocytes.
  • the cells were then centrifuged three times in RPMI-1640 medium for washing and were resuspended in an RPMI-1640 medium.
  • mitomycin C KYOWA HAKKO KOGYO Co., Ltd.
  • the cells were centrifuged three times in RPMI-1640 medium for washing and were resuspended in an RPMI-1640 medium so that the medium would contain 2.5 ⁇ 10 8 cells/mL.
  • This suspension served as a “stimulation cell suspension.”
  • 20 ⁇ L (5 ⁇ 10 6 cells/mouse) of the stimulation cell suspension was subcutaneously injected into the right hind footpad of 6 to 12 week old male C3H/HeN mice (CLEA JAPAN Inc., CHARLES RIVER JAPAN Inc., or JAPAN SLC Inc.).
  • a group of mice were injected with RPMI-1640 medium alone. 4 days after the injection, right popliteal lymph nodes were collected and were weighed on a Mettler AT201 electronic scale (METTLER TOLEDO Co., Ltd.).
  • Each animal was intraperitoneally administered a test compound once a day for four consecutive days starting on the day of the injection of the stimulation cells (i.e., total of 4 times).
  • a group of the animals were administered the same solvent as that used in the preparation of each test compound. The results are shown in Table 16 below:
  • each of the compounds of the present invention represented by the general formula (1) has proven to be effective in the animal model.
  • the present invention has been devised in recognition of the fact that the novel amino alcohol derivatives with a diarylsulfide or diarylether group exhibit strong immunosuppressive effects, the effects particularly significant when one of the aryl groups includes, at its para-position, a carbon chain with an amino alcohol group and the other aryl group includes a substituent at its meta-position.
  • Effective immunosuppressors the compounds of the present invention have a great potential as a prophylactic or therapeutic agent against rejection in organ or bone marrow transplantation, autoimmune diseases, rheumatoid arthritis, psoriasis, atopic dermatitis, bronchial asthma, pollinosis and various other diseases.

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